Use of conformational analysis as a design element in diversity-oriented organic synthesis

Small molecules can be used to study biology analogously to the use of mutations. The full potential of this chemical genetic approach will likely be realized through greater access to structurally complex and diverse small molecules. Diversity-oriented organic synthesis will play an important in bringing small molecules to bear on the analysis of biological phenomena. Diversity-oriented organic synthesis aims to generate many structurally complex molecules having different skeletons in a small number of steps; yet conceiving such synthetic schemes is a challenging proposition. As conformational analysis has been used strategically in the planning of target-oriented syntheses, we propose that this type of analysis is applicable to the design of diversity-oriented synthetic pathways. Described in this thesis are three different diversity-oriented syntheses of complex small molecules; each of which was designed based on consideration of the conformational preferences of cyclic and acyclic molecules. In the second chapter, rigorous testing of a conformational analysis-based design strategy for the efficient, stereocontrolled syntheses of densely functionalized macrocycles is described. The third chapter recounts highly efficient solution and solid phase syntheses of natural-product like, polycyclic molecules. The key to the efficiency of this synthetic scheme was the pair-wise use of complexity generating multi-component and cyclization reactions. Careful consideration of the conformational preferences of intermediates in the forward synthetic analysis led to the recognition of these unusual reaction productreaction substrate relationships. While the second and third chapters illustrate real progress towards planning efficient syntheses of many structurally complex molecules, the final chapter points the way to the design of synthetic pathways that yield many molecules of different and complex skeletons. It describes the discovery of a synthetic pathway that yields structurally complex molecules of distinct connectivities from two diastereomeric progenitors. Systematic studies of this branching pathway revealed that the bifurcation can be ascribed to a conformation-biasing stereogenic center. The conformational analysis-based principles illustrated in each of these syntheses will serve as bases for the planning of future diversity-oriented organic syntheses. Molecules from such syntheses may be used to illuminate poorly understood biological phenomena or to remedy human maladies.